Clinical Therapeutics/Volume 33, Number 4, 2011
Effects of Varenicline in Adult Smokers: A Multinational,
24-Week, Randomized, Double-Blind, Placebo-Controlled Study
Chris T. Bolliger, MD, PhD1; Jaqueline S. Issa, MD, PhD2; Rodolfo Posadas-Valay, MD3;
Tarek Safwat, MD, FCCP4; Paula Abreu, DR.PH5; Eurico A. Correia, MD, MSc6;
Peter W. Park, PhD5; and Pravin Chopra, MD5
1
Respiratory Research Unit, Faculty of Health Sciences, University of Stellenbosch, Cape Town, South
Africa; 2Heart Institute, University of São Paulo, São Paulo, Brazil; 3Hospital Universitario UANL,
Centro de Prevención y Rehabilitación de Enfermedades Pulmonares Crónicas, Monterrey, Mexico;
4
Department of Chest Medicine, Ain Shams University, Cairo, Egypt; 5Pfizer Inc, New York, New York;
and 6Pfizer Inc, São Paulo, Brazil
ABSTRACT
Background: Prevalence rates of smoking are rising
in developing countries. Previous trials evaluating the
efficacy and tolerability of the smoking-cessation medication varenicline have used largely participants of
Caucasian origin.
Objective: This study was conducted to evaluate the
efficacy and tolerability of varenicline in populations
of participants from Latin America, Africa, and the
Middle East to investigate potential differences in the
therapeutic response to varenicline.
Methods: This multinational, randomized, doubleblind, placebo-controlled trial was conducted at 42
centers in 11 countries (Latin America: Brazil, Colombia, Costa Rica, Mexico, and Venezuela; Africa: Egypt
and South Africa; Middle East: Jordan, Lebanon,
Saudi Arabia, and the United Arab Emirates). Participants were male and female smokers aged 18 to 75
years who were motivated to stop smoking; smoked
ⱖ10 cigarettes/d, with no cumulative period of abstinence ⬎3 months in the previous year; and who had no
serious or unstable disease within the previous 6
months. Subjects were randomized in a 2:1 ratio to
receive varenicline 1 mg or placebo, BID for 12 weeks,
with a 12-week nontreatment follow-up. Brief smoking-cessation counseling was provided. The main outcome measures were carbon monoxide– confirmed
continuous abstinence rate (CAR) at weeks 9 to 12 and
weeks 9 to 24. Adverse events (AEs) were recorded for
tolerability assessment.
Results: Overall, 588 subjects (varenicline, 390; placebo, 198) were randomized and treated. The mean
(SD) ages of subjects in the varenicline and placebo
groups were 43.1 (10.8) and 43.9 (10.8) years, respec-
April 2011
tively; 57.7% and 65.7% were male; and the mean
(SD) weights were 75.0 (16.0) and 76.7 (16.3) kg
(range, 40.0 –130.0 and 45.6 –126.0 kg). CAR at
weeks 9 to 12 was significantly higher with varenicline
than with placebo (53.59% vs 18.69%; odds ratio
[OR] ⫽ 5.76; 95% CI, 3.74 – 8.88; P ⬍ 0.0001), and
this rate was maintained during weeks 9 to 24
(39.74% vs 13.13%; OR ⫽ 4.78; 95% CI, 2.97–7.68;
P ⬍ 0.0001). Nausea, headache, and insomnia were
the most commonly reported AEs with varenicline and
were reported numerically more frequently in the varenicline group compared with the placebo group. Serious AEs (SAEs) were reported in 2.8% of varenicline
recipients compared with 1.0% in the placebo group,
with 6 subjects reporting psychiatric SAEs compared
with none in the placebo group.
Conclusion: Based on these data, varenicline was apparently efficacious and generally well tolerated as a
smoking-cessation aid in smokers from selected sites in
LatinAmerica,Africa,andtheMiddleEast.ClinicalTrials.
gov identifier: NCT00594204. (Clin Ther. 2011;33:
465–477) © 2011 Published by Elsevier HS Journals, Inc.
Key words: continuous abstinence rate, randomized
trial, smoking cessation, varenicline.
INTRODUCTION
Smoking remains an important preventable cause of
disease, and the estimated disease burden attributable
Accepted for publication April 19, 2011.
doi:10.1016/j.clinthera.2011.04.013
0149-2918/$ - see front matter
© 2011 Published by Elsevier HS Journals, Inc.
465
Clinical Therapeutics
Table I. Prevalence of tobacco use and dates of treatment availability in selected countries.
Daily Smoking Prevalence, %
Date of Drug Availability
Region/Country
Men
Women
All
Varenicline
Bupropion
NRT
Latin America
Venezuela
Costa Rica
Colombia
Brazil
Mexico
35.9
29.0
26.8
21.6
12.9
21.4
9.7
11.3
13.0
4.7
23.0*
6.0*
N/A
17.2†
18.5‡
May 2008
October 2007
June 2007
August 2007
December 2006
2000
1990
1989
1997
1989
1978
1978
1978
1978
1978
Africa
Egypt
South Africa
45.4
23.2
12.1
7.7
14.0*
16.0*
June 2009
N/A
N/A
2003
N/A
1998
Middle East
Jordan
Lebanon
United Arab Emirates
Saudi Arabia
50.5
42.3
17.3
14.4
8.3
30.6
1.3
4.9
36.0*
17.0*
8.0*
7.0*
June 2008
June 2008
September 2007
August 2008
N/A
2003
2003
N/A
2004
2007
1998
Available
NRT ⫽ nicotine-replacement therapy; N/A ⫽ treatment not available.
*Data from reference.7
†
Data from reference.8
‡
Data from reference.9
to smoking is ⬎6 million premature deaths each year
worldwide.1 If current trends continue, the estimated
deaths from tobacco during the 21st century will be 1
billion.2 Smokers trying to quit frequently fail due to
the addictive effect of nicotine. Pharmaceutical aids
have been used successfully to help smokers quit; for
example, nicotine-replacement therapy (NRT) has
been found to increase the rate of abstinence by 50% to
70% compared with placebo.3 Currently, 3 compounds are considered first-line therapies: NRT in various formulations; the antidepressant bupropion; and,
more recently, varenicline, an ␣4␤2 nicotinic acetylcholine receptor partial antagonist.4 Based on data from various published reports in the 2008 US Clinical Practice
Guideline,4 varenicline seems to be associated with higher
abstinence rates than NRT5 or bupropion.6 However,
these reports came from studies mainly conducted in the
United States, Europe, and Asia.
Based on a MEDLINE search of studies published
through 2008, no clinical trials of varenicline had been
conducted in Latin America, Africa, or the Middle East.
Nicotine use varies within these regions (Table I),7–10 and
466
while smoking rates are declining in the developed world,
they are still rising in developing countries.2
Varenicline may have benefits in smokers in these
countries with often-limited access to smoking-cessation
interventions. While results from pivotal Phase III clinical
trials are sufficient for many national health agencies to
render a decision on the approval of a medication, clinical
data from local patients are useful for assisting physicians
in making individual treatment decisions. It is therefore
important to determine the efficacy and tolerability of
varenicline in smokers in unstudied populations. The aim
of the present study was to evaluate the efficacy and tolerability of varenicline as an aid for smoking cessation in
populations of cigarette smokers in Latin America, Africa, and the Middle East.
PARTICIPANTS AND METHODS
Study Design
This multinational, 24-week, randomized, doubleblind, placebo-controlled efficacy and tolerability trial
of varenicline was conducted from April 10, 2008, to
August 17, 2009, at sites in Latin America (Brazil [7
Volume 33 Number 4
C T. Bolliger et al.
Table II. Number of study sites and participants,
by country.
Region/Country
Participants
Sites (N ⫽ 42) (N ⫽ 588)
Latin America
Brazil
Venezuela
Mexico
Colombia
Costa Rica
7
4
3
2
1
96
56
100
28
21
Africa
South Africa
Egypt
13
1
130
50
6
60
2
2
1
26
11
10
Middle East
United Arab
Emirates
Lebanon
Saudi Arabia
Jordan
sites], Venezuela [4], Mexico [3], Colombia [2], and
Costa Rica [1]); Africa (South Africa [13] and Egypt
[1]); and the Middle East (United Arab Emirates [6],
Lebanon [2], Saudi Arabia [2], and Jordan [1]) (Table
II). The investigative sites were smoking cessation clinics, medical centers, and hospitals.
The primary objective of this study was to evaluate
the efficacy of 12 weeks of varenicline treatment (1
week of dose titration [0.5 mg once daily for 3 days
followed by 0.5 mg BID for 4 days] followed by 11
weeks of varenicline 1 mg BID) compared with placebo
for smoking cessation. Secondary objectives were to
compare abstinence from cigarette smoking in the 12week nontreatment follow-up period, and to evaluate
the tolerability of varenicline.
The study was conducted in accordance with the
ethical principles of the Declaration of Helsinki,11 was
approved by the institutional review boards and independent ethics committees at each of the study sites,
and was conducted in compliance with the standards
on good clinical practice developed by the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for
Human Use (ICH).12 All of the participants provided
April 2011
written informed consent before any study procedures
were conducted or study medication was administered.
Participants
Eligible participants were male and female smokers
aged 18 to 75 years, with a body mass index of 15 to 38
kg/m2 (and a weight of at least 45.5 kg), who were
motivated to stop smoking and had smoked a mean of
ⱖ10 cigarettes/d during the previous 12 months and
during the month before the screening visit, with no
cumulative period of abstinence ⬎3 months in the previous 12 months. Women of childbearing potential
were included provided that they were not pregnant or
breastfeeding and that they had agreed to practice an
effective method of contraception through to at least
30 days after the administration of the last dose of
study medication.
Smokers with serious or unstable disease within the
6 months before study entry (including cardiovascular
disease, cerebrovascular disorders, and neurologic disorders) were not eligible for participation. Other exclusion criteria included a diagnosis of, or treatment
for, depression during the previous 12 months; a history of or current psychosis, panic disorder, or bipolar
disorder; severe chronic obstructive pulmonary disease; uncontrolled hypertension or systolic blood pressure (BP) ⬎150 mm Hg or diastolic BP ⬎95 mm Hg at
the screening or baseline visit; a clinically significant
endocrine disorder or gastrointestinal disease; clinically significant hepatic or renal impairment or other
clinically significant laboratory abnormality; a history
of a cancer (excluding basal cell or squamous cell carcinoma); a history of a clinically significant allergic
reaction to a medication; a history of drug (with the
exception of nicotine) or alcohol abuse or dependence
within the previous 12 months; use of NRT, bupropion, clonidine, or nortriptyline within the previous 6
months; and/or participation in another study of an
experimental drug for smoking cessation within the
previous 12 months, or treatment with any medications that might interfere with the outcome of the trial.
Screening
The screening visit took place 3 to 14 days before
the baseline visit (week 0). Data on demography, medical history, physical examination, vital signs (temperature, BP, heart rate, and respiratory rate), weight and
height, ECG, pregnancy, biochemistry, hematology,
and urinalysis were obtained. Pregnancy tests were
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Clinical Therapeutics
conducted by qualitative determination of serum or
urine chorionic gonadotropin in women of childbearing potential at a local laboratory within 24 hours before study entry. Biochemistry testing included sodium, potassium, chloride, bicarbonate, blood urea
nitrogen or serum urea, creatinine, glucose, calcium,
inorganic phosphorus, aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, alkaline
phosphatase, total bilirubin, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, albumin, and total protein. Hematology testing included absolute blood cell counts with
differential, including neutrophils, bands, lymphocytes,
monocytes, eosinophils, and basophils; and hemoglobin,
hematocrit, and platelet count. Urinalysis assessments
were conducted using a dipstick and included specific
gravity, pH, glucose, ketones, protein, hemoglobin, urobilinogen, eosinophils, urine bilirubin, nitrate, and leukocyte esterase. Samples for pregnancy, biochemistry, hematology, and urinalysis were sent to a local laboratory
for analysis. A smoking history was also obtained, and
eligible participants completed the Fagerström Test for
Nicotine Dependence (FTND)13 to determine the extent
of nicotine dependence. The FTND is a 6-item test that
scores nicotine dependence on a scale of 0 to 10, with
higher scores reflecting greater nicotine dependence.
Interventions
Using a block randomization within each site, eligible participants were randomly assigned in a 2:1 ratio
to receive varenicline or placebo. Active drug and placebo (provided as matching tablets) were orally administered with water. Identification numbers and study
treatments were assigned to participants at the screening visit using a Web-based or telephone call-in drugmanagement system directed by the sponsor. All of the
study personnel and participants were blinded to treatment assignment until the end of the nontreatment follow-up phase. All study medications and procedures
were provided to participants free of charge.
Study treatment was dispensed at the baseline clinic
visit (randomization), and participants were given You
Can Quit Smoking,14 an educational booklet on smoking cessation available in English, Spanish, Portuguese,
and Arabic. Participants also received brief 1-on-1
smoking-cessation counseling (up to 10 minutes) in
accordance with the Preventive Services Task Force
guideline,15 which was offered to participants at each
subsequent visit (clinic and telephone) during the treat-
468
ment and follow-up phases. Participants were assigned
a target quit date (TQD) (defined as the day on which
the participant agreed to initiate smoking abstinence),
which coincided with the first scheduled treatment visit
(week 1). Each participant was contacted by telephone
and reminded of his or her study participation and
received brief counseling 3 days after the TQD. Participants returned for clinic visits at weeks 2, 3, 4, 6, 8, 10,
and 12 during the treatment phase and at weeks 13, 16,
20, and 24 during the nontreatment follow-up period.
Assessments by telephone were conducted at weeks 14,
18, and 22.
Vitals signs and weight were measured at each clinic
visit throughout the study period. Physical examination, ECG, blood chemistry, hematology, and urinalyses were repeated at week 12 or at early termination.
Use of nicotine-containing products, changes in concurrent medications, and reports of adverse events
(AEs) were assessed at each study visit. Those who
discontinued study treatment prematurely were encouraged to participate in the remaining study visits
through the nontreatment follow-up period.
Smoking Status
Smoking status was assessed using the nicotine-use
inventory (NUI) (a self-completion questionnaire documenting the use of cigarettes and other nicotine-containing products, designed for, and implemented in,
previous varenicline studies6,16), which was administered at baseline and at all subsequent study visits. Selfreported smoking abstinence was confirmed by endexpiratory exhaled carbon monoxide (CO) ⱕ10 ppm
at each clinic visit using a breath CO monitor (Micro
IV Smokerlyzer, Bedfont Scientific Ltd, Rochester,
United Kingdom), which is considered an appropriate
measure for biochemical verification and has been used
in previously published clinical trials of smoking-cessation treatments.17,18 Participants with CO measurements ⬎10 ppm were considered nonabstinent during
the period associated with the measurement.
Adverse Events
All reported or observed AEs were documented on
case-report forms, which were provided, collected, and
monitored by the sponsor and followed up from the
administration of the first dose of study treatment until
resolution or the end of the study. AEs were reported
descriptively using the coding from the Medical Dictionary for Regulatory Activities (MedDRA) version
Volume 33 Number 4
C T. Bolliger et al.
12. All AEs were tabulated using the Treatment Emergent Signs and Symptoms (TESS) algorithm. Descriptive statistics rather than inferential statistics were used
to compare treatment arms with respect to AE data due
to challenges of controlling Type I error in multiple
comparisons.
Serious AEs (SAEs) and severe AEs were also documented on case-report forms and reported to the sponsor. The US Food and Drug Administration and ICH
definition of an SAE was used in this trial. Thus, an AE
was recorded as an SAE if it resulted in death, was
life-threatening, required inpatient hospitalization or
prolongation of existing hospitalization, resulted in
persistent/significant disability/incapacity, and/or led
to congenital anomaly/birth defect. An AE was considered severe if it interfered significantly with subject’s
usual functioning.
Outcomes Measures
Primary End Point
The primary end point was the CO-confirmed
4-week continuous abstinence rate (CAR) for weeks 9
to 12, with CAR defined as the proportion of participants who maintained complete abstinence (not
even a puff) from the use of cigarettes and other
nicotine-containing products during this period.
Smoking abstinence was assessed using the NUI and
was verified using measurements of end-expiratory
exhaled CO.
Secondary End Points
Secondary end points included the CO-confirmed
CAR during weeks 9 to 24; 7-day point prevalence of
nonsmoking at weeks 12 and 24; and the incidence rate
of AEs, premature discontinuations during the study,
and clinically significant changes in vital signs. The
7-day point prevalence at weeks 12 and 24 was defined
as the proportion of participants who had not used
cigarettes or any other nicotine-containing product
during the 7 days before the assessment.
Statistical Analysis
All of the primary and secondary end points were
analyzed in the full-analysis population, defined as participants who took at least 1 dose, including a partial
dose, of study medication.
All statistical testing was 2-sided with a Type I error
rate of 0.05. A step-down procedure was used in the
analysis of the primary and key secondary end points
to preserve the Type I error rate of 0.05. No adjust-
April 2011
ments were made for the analysis of multiple other
secondary end points. The hierarchy of comparisons
between varenicline and placebo was as follows: (1) the
4-week CAR for weeks 9 to 12 and (2) the CAR for
weeks 9 to 24. SAS version 8.2 (SAS Institute Inc, Cary,
North Carolina) was used for all analyses.
Abstinence end points were analyzed as binary data
using the logistic regression model, which included the
main effects of treatment group and investigative country as independent variables. Treatment-by-center interaction was investigated; however, the reported P
values were based on the main-effects model. All significance tests were 2-tailed using a significance level of
0.05.
It was important to power this study for the primary
(CAR at weeks 9 –12) and key secondary (CAR at
weeks 9 –24) end points. To achieve 90% power to
detect significant differences in the secondary end point
in a 2-group, continuity-corrected ␹2 test with ␣ ⫽
0.05 for the comparison of varenicline with placebo,
the calculated sample size was a minimum of 270 participants (180 in the varenicline group and 90 in the
placebo group). The actual sample size of 588 used in
this study provided ⱖ95% power to detect significant
differences in the primary end point. Estimates for expected varenicline and placebo CAR at weeks 9 to 12
and weeks 9 to 24 were based on results from a similarly designed previously published study19 but are
more conservative.
Only participants who attended clinic visits and
met both the NUI and CO criteria were considered
abstinent. Participants who discontinued from the
study and were lost to follow-up for subsequent visits were assumed to be smokers for the remainder of
the study. In binary responder assessments, subjects
who discontinued were represented in the denominator but not in the numerator, regardless of smoking status at the time of discontinuation, which
might be considered a worst-case-carried-forward
analysis and represents a conservative approach to
the imputation of missing data.
RESULTS
Participant Disposition
Of the 689 individuals who were screened, 593
(86.1%) were randomized (Figure 1). Overall, 588
participants received at least 1 dose of study treatment
(varenicline, 390; placebo, 198) and were included in
the full-analysis population. Of the 5 participants who
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Clinical Therapeutics
Individuals screened
(n = 689)
Excluded (n = 96)
Did not meet inclusion criteria (n = 45)
Refused to participate (n = 18)
Lost to follow-up (n = 8)
Protocol violation (n = 1)
Other (n = 24)
Randomized
(n = 593)
Assigned to receive varenicline (n = 394)
Refused to participate further (n = 3)
Lost to follow-up (n = 1)
Received allocated intervention (n = 390†)
Discontinued study
(treatment phase only)
(n = 44)
Assigned to receive placebo (n = 199)
Lost to follow-up (n = 1)
Received allocated intervention (n = 198†)
Discontinued from treatment (n = 54)
Lack of efficacy (n = 3)
Adverse events related to study drug (n = 12)
Adverse events not related to study drug (n = 3)
Refused to participate further (n = 23)
Lost to follow-up (n = 9)
Other (n = 4)
Discontinued from treatment (n = 44)
Lack of efficacy (n = 4)
Adverse events related to study drug (n = 3)
Lost to follow-up (n = 5)
Refused to participate further (n = 29)
Other (n = 3)
Discontinued study (non-treatment phase) (n = 10)
Adverse events related to study drug (n = 1)
Adverse events not related to study drug (n = 1)
Refused to participate further (n = 2)
Lost to follow-up (n = 5)
Other (n = 1)
Discontinued study (non-treatment phase)
(n = 1)
Adverse events related to study drug (n = 1)
Completed study
(n = 336)
Discontinued study
(treatment phase only)
(n = 41)
Completed study
(n = 156)
Figure 1. Participant disposition. *Included participants who did not meet the inclusion criteria, had 1 or more
protocol violations, or “other.” †All participants who received at least 1 dose or partial dose of study
medication were included in the efficacy and tolerability analyses.
were randomized but did not receive study treatment, 3
were no longer willing to participate (all in the varenicline group) and 2 were lost to follow-up (varenicline, 1; placebo, 1). A total of 336 of 394
(85.3%) participants assigned to receive varenicline
and 156 of 199 (78.4%) assigned to receive placebo
completed the study. Overall, the study-completion
rates at week 24 were 336 of 390 (86.2%) in the
varenicline group and 156 of 198 (78.8%) in the
placebo group. Overall, 54 (13.8%) participants in
the verenicline and 42 (21.2%) participants in the
placebo arm discontinued the study.
Participant enrollment per region was as follows:
Latin America, 301 (51.2%); Africa, 180 (30.6%); and
the Middle East, 107 (18.2%) (Table II). The demographic characteristics were statistically similar between the 2 treatment groups (Table III). The mean
470
ages of the participants were 43.1 years (range, 18 – 69
years) and 43.9 years (range, 20 –71 years) in the varenicline and placebo groups, respectively. The majority of the participants in the 2 groups were male (225
[57.7%] and 130 [65.7%]). The mean weights of participants in the varenicline and placebo groups were
75.0 and 76.7 kg, respectively. There were no statistically significant differences in smoking history between
the 2 treatment groups. The mean numbers of cigarettes smoked per day over the month before the study
were 23.8 and 23.7 in the varenicline and placebo
groups. The mean number of years that the participants smoked were 25.0 and 26.8, and the mean ages
at which the participants started smoking were 17.7
and 16.7 years. The varenicline group had a mean (SD)
FTND score of 6.0 (2.2), and the placebo group had a
mean score of 6.1 (2.0) of a possible total score of 10.
Volume 33 Number 4
C T. Bolliger et al.
Table III. Baseline demographic and clinical characteristics of the study population.*
Characteristic
Varenicline
(n ⫽ 390)
Placebo
(n ⫽ 198)
Age, y
Mean (SD)
Range
43.1 (10.8)
18–69
43.9 (10.8)
20–71
Sex, no. (%)
Male
Female
225 (57.7)
165 (42.3)
130 (65.7)
68 (34.3)
Race, no. (%)†
White
Black
Asian
Other‡
118 (30.3)
26 (6.7)
26 (6.7)
220 (56.4)
62 (31.3)
15 (7.6)
9 (4.5)
112 (56.6)
Weight, kg
Mean (SD)
Range
75.0 (16.0)
40.0–130.0
76.7 (16.3)
45.6–126.0
Height, cm
Mean (SD)
Range
168.2 (9.3)
134.0–193.0
169.4 (9.6)
143.0–203.0
26.4 (4.8)
16.8–43.6
26.6 (4.4)
17.0–38.6
17.7
9.0–41.0
16.7
8.0–37.0
25.0
1.0–57.0
26.8
6.0–58.0
23.8
10.0–90.0
23.7
10.0–80.0
12.3
0.1–57.0
13.8
0.0–50.0
Body mass index, kg/m2
Mean (SD)
Range
Risk factors
Age started smoking, y
Mean
Range
Years of smoking, y
Mean
Range
Cigarettes/d over previous
month
Mean
Range
Years smoking at this rate
Mean
Range
Lifetime serious quit
attempts,§ no. (%) of
participants
0
1
2
ⱖ3
Fagerström score13 for
nicotine dependence, mean
(SD)储
Efficacy
Continuous Abstinence
The CO-confirmed CAR at weeks 9 to 12 was significantly higher with varenicline (53.59%) compared
with placebo (18.69%) (odds ratio [OR] ⫽ 5.76; 95%
CI, 3.74 – 8.88; P ⬍ 0.0001) (Figure 2). CAR at weeks
9 to 24 was significantly higher with varenicline compared with placebo (39.74% vs 13.13%; OR ⫽ 4.78;
95% CI, 2.97–7.68; P ⬍ 0.0001). Because the 2 treatment groups received identical smoking-cessation
counseling (10-minute duration), any effect of counseling on efficacy outcomes would be expected to have
been similar between the 2 groups. Treatment-by-center interactions were found to be nonsignificant. Exploratory logistic regression analyses showed no statistically significant treatment differences based on
participant age, sex, or FTND score.
Point Prevalences of Abstinence Rates
212 (54.4)
99 (25.4)
27 (6.9)
52 (13.3)
109 (55.1)
54 (27.3)
13 (6.6)
22 (11.1)
6.0 (2.2)
6.1 (2.0)
*No significant between-group differences were found.
†
Percentages may not total 100 due to rounding.
‡
Included Arab, Caucasian, Hispanic, and mixed races.
§
Number of quit attempts and/or number of quit methods used.
储
Range: 0 ⫽ no nicotine dependence to 10 ⫽ highest nicotine
dependence.
April 2011
There were small but nonsignificant differences in
smoking history between the 3 geographic regions,
with the mean number of cigarettes/d smoked over the
previous month being highest in the Middle East (27.4
and 29.5 in the active-treatment group vs placebo; Africa, 23.7 vs 23.4; Latin America, 22.7 vs 21.7), and
the mean FTND scores being highest in the African
region (6.7 vs 6.4; Middle East, 6.3 vs 6.0; Latin America, 5.5 vs 5.9).
Concurrent use of medication was statistically similar between the 2 treatment groups. Approximately
67.4% of the participants in the varenicline group and
65.7% of participants in the placebo group used some
form of concurrent drug treatment, the most common
of which were analgesics (24.1% and 22.2% in the
varenicline and placebo groups, respectively).
The 7-day point prevalences of abstinence rates
were significantly higher with varenicline compared
with placebo at the end of treatment (week 12; 56.4%
vs 22.7% [P ⬍ 0.0001]) and at the end of follow-up
(week 24; 47.4% vs 19.2% [P ⬍ 0.0001]). At all assessments, the 7-day point prevalences of abstinence
rates were significantly higher with varenicline compared with placebo (Figure 3).
Tolerability
All-causality, treatment-emergent AEs were reported in 262 (67.2%) participants in the varenicline
group and 108 (54.5%) participants in the placebo
group (Table IV). The treatment-emergent AEs most
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Clinical Therapeutics
40
Varenicline 1 mg BID (n = 390)
Placebo (n = 198)
CAR (%)
30
20
10
0
Weeks 9–12*
Weeks 9–24†
Figure 2. Carbon monoxide (CO)-confirmed smoking continuous abstinence rates (CAR) at
weeks 9 to 12 and weeks 9 to 24. At each
visit from week 9 through the given time
point, these participants reported no use
of cigarettes or other nicotine-containing
products since the previous study visit (on
the nicotine-use inventory [a self-completion questionnaire documenting the use of
cigarettes and other nicotine-containing
products, designed for, and implemented
in, previous varenicline studies6,16]) and
did not have CO ⬎10 ppm (when assessed
at a clinic visit). *Odds ratio (OR) ⫽ 5.76;
95% CI, 3.74 – 8.88; P ⬍ 0.0001; †OR ⫽
4.78; 95% CI, 2.97–7.68; P ⬍ 0.0001
(ORs and P values were obtained from logistic regression modeling, including the
main effects of treatment and country).
frequently reported (5% or more of the participants)
with varenicline compared with placebo are shown in
Table V. Nausea was the most commonly reported AE
in the varenicline group (103 [26.4%]), followed by
headache (64 [16.4%]), insomnia (50 [12.8%]), and
constipation (23 [5.9%]).
Severe AEs were reported in 32 participants (8.2%)
in the varenicline group and in 10 participants (5.1%)
in the placebo group (Table IV). Overall, AEs that
resulted in permanent study discontinuations were
reported in 19 participants, with a 4.1% incidence of
discontinuations in varenicline-treated participants
(n ⫽ 16) versus 1.5% in placebo-treated participants
(n ⫽ 3).
472
All-causality, treatment-emergent psychiatric AEs
included anxiety disorders (23 [5.9%] in the varenicline group vs 17 [8.6%] in the placebo group); depressed mood disorders (12 [3.1%] in the varenicline
group vs 7 [3.5%] in the placebo group); and suicidal
and self-injurious behaviors (2 [0.5%] in the varenicline group vs 0 in the placebo group) (Table VI).
There were 2 cases of suicidal ideation in the varenicline group (0.5%), 1 of which was considered to be
treatment related. In addition, a 52-year-old male participant reported a suicide attempt during the nontreatment phase, at 49 days after the administration of last
dose of study drug; the event was considered unrelated
to the study drug. Overall, 4 psychiatric AEs in 3 participants who received varenicline were reported as
SAEs (suicidal ideation and depressed mood, suicidal
ideation, and panic attack).
Across the 2 treatment groups, 13 participants
(varenicline, 11 [2.8%]; placebo, 2 [1.0%]) reported
20 SAEs during the 12 weeks of treatment or within
30 days of the administration of the last dose of
study medication (Table IV). In the varenicline
group, SAEs were (by preferred term) abortion; hypersensitivity; overdose; bronchitis and asthma; nasal septum deviation; suicidal ideation and depressed
mood; suicidal ideation; tachycardia, bradycardia,
and dyspnea; panic attack; injury; and appendicitis.
Figure 3. Seven-day point prevalences of abstinence. Abstinence from any nicotinecontaining product in the previous 7
days was carbon monoxide-confirmed at
clinic visits (solid symbols). Assessments
by telephone were conducted at weeks
14, 18, and 22 (open symbols). *P ⬍
0.0001 versus placebo.
Volume 33 Number 4
C T. Bolliger et al.
Table IV. Adverse events (AEs). Data are number
(%) of participants.*
Parameter
Varenicline Placebo
(n ⫽ 390) (n ⫽ 198)
Any AE
262 (67.2) 108 (54.5)
Serious AE†
11 (2.8)
2 (1.0)
‡
Severe AE
32 (8.2) 10 (5.1)
Treatment discontinuation
All-causality AE
16 (4.1)
3 (1.5)
Treatment-related AE
12 (3.1)
3 (1.5)
*Includes data up to 30 days after the administration of
the last dose of study drug. Includes all AEs reported in
the Medical Dictionary for Regulatory Activities System Organ
Class of Psychiatric Disorders, Version 12.
†
Defined as any AE that resulted in death, was life-threatening, required inpatient hospitalization or prolongation of
existing hospitalization, resulted in persistent/significant
disability/incapacity, and/or led to congenital anomaly/
birth defect.
‡
Defined as any AE that significantly interfered with the
subject’s usual functioning.
In the placebo group, SAEs were thyroid neoplasm;
and peritonitis, appendicitis, and diverticulitis.
None of the participants died during the study
period.
The overdose in the varenicline group was reported
in a 51-year-old man with a history of cervical spondylosis and depression, who was experiencing a severe
frontal headache. In an attempt to treat the headache,
the subject took 14 carbamazepine and 2 paracetamol/
codeine phosphate tablets on the same day. He was
found semiconscious, was admitted to a hospital, and
was diagnosed as having had a drug overdose. The
subject was given IV fluids but no medication was administered. He was discharged in stable condition and
remained in the study. The event was considered by the
investigator as unrelated to study drug.
An abortion was reported in a 32-year-old woman
in the varenicline group who had discovered that she
was pregnant ⬃1 month into the study, immediately
discontinued treatment, and 9 days after discontinuation experienced bleeding and a confirmed abortion at
the hospital. The investigator concluded that a contributory role of the study medication could not be
excluded.
April 2011
A spontaneous abortion was reported in a 25-yearold woman in the varenicline group who had become
pregnant ⬃1 month into the study, discontinued treatment, and 2 months after discontinuation experienced
an abortion; the investigator did not consider the event
related to the study drug.
DISCUSSION
In this randomized, placebo-controlled study in smokers from Latin America, Africa, and the Middle East,
varenicline was apparently efficacious in achieving
smoking cessation, and was considered generally well
tolerated. In this study, varenicline was associated with
a significantly higher CAR for the last 4 weeks of treatment (CAR weeks 9 –12; 53.59% vs 18.69%; OR ⫽
5.76; 95% CI, 3.74 – 8.88; P ⬍ 0.0001) compared with
placebo. Importantly, varenicline also was associated
with a significantly higher CAR at weeks 9 to 24
(39.74% vs 13.13%; OR ⫽ 4.78; 95% CI, 2.97–7.68;
P ⬍ 0.0001) compared with placebo. The 7-day point
prevalences of abstinence at the end of treatment (week
12) and at the end of follow-up (week 24) were also
significantly higher with varenicline compared with
placebo.
Table V. Most frequently reported treatment-emergent adverse events (AE) (all-causality).
Data are number (%) of participants.*
AE
Varenicline Placebo
(n ⫽ 390) (n ⫽ 198)
Gastrointestinal disorders
Nausea
Constipation
151 (38.7) 43 (21.7)
103 (26.4) 16 (8.1)
23 (5.9) 10 (5.1)
Nervous system disorders
Headache
92 (23.6) 41 (20.7)
64 (16.4) 24 (12.1)
Psychiatric disorders
Insomnia
Anxiety
90 (23.1) 30 (15.2)
50 (12.8) 13 (6.6)
16 (4.1) 15 (7.6)
Infections and infestations
Influenza
76 (19.5) 39 (19.7)
14 (3.6) 12 (6.1)
*All observed or self-reported AEs that occurred in ⱖ5% of
participants. Includes data up to 30 days after the administration of the last dose of study drug. Includes all AEs
reported in the Medical Dictionary for Regulatory Activities System Organ Class of Psychiatric Disorders, Version 12.
473
Clinical Therapeutics
Table VI. Treatment-emergent psychiatric adverse events (AE) (all-causality).*
AE
Varenicline
(n ⫽ 390)
Placebo
(n ⫽ 198)
Sleep disorders or disturbances
Abnormal dreams, insomnia, nightmare, sleep disorder
66 (16.9)
15 (7.6)
Anxiety disorders or symptoms
Agitation, anxiety, nervousness, obsessive thoughts, stress
23 (5.9)
17 (8.6)
Depressed mood disorders or disturbances
Depression, depressed mood, depressive symptom, dysthymia
12 (3.1)
7 (3.5)
Other mood disorders or disturbances
Anger, flat affect, mood altered
5 (1.3)
4 (2.0)
Suicidal and self-injurious behaviors
Suicidal ideation
2 (0.5)
0
Sexual dysfunction and fertility disorders
Erectile dysfunction
3 (0.8)
1 (0.5)
2 (0.5)
1 (0.5)
1 (0.3)
0
Disturbance in attention
Disturbances in behavior
Aggression
*Includes data up to 30 days after the administration of the last dose of study drug. Includes all AEs reported in the Medical
Dictionary for Regulatory Activities System Organ Class of Psychiatric Disorders, version 12. Each row represents a higher-level
group term, which is a combination of the individual symptom terms listed below the group term.
Comparison With Other Studies
The OR for CAR at weeks 9 to 12 in this study
(OR ⫽ 5.76; 95% CI, 3.74 – 8.88; P ⬍ 0.0001) was
higher than those observed in previously published
clinical trials that measured the CAR of varenicline
versus placebo in generally healthy smokers.6,16,19,20
In 2 early Phase III studies in white subjects, CAR at
weeks 9 to 12 was reported to be 43.9% with varenicline versus 17.6% with placebo (OR ⫽ 3.85; 95% CI,
2.7–5.5; P ⬍ 0.001)16 and 44.0% versus 17.7%, respectively (OR ⫽ 3.85; 95% CI, 2.7–5.5; P ⬍ 0.001).6
More importantly, the OR for CAR at weeks 9 to 24
compared favorably with those from all of the previously published varenicline studies found in the MEDLINE search, including 2 studies in nonwhite populations.19,20 The CIs of the ORs, however, overlapped.
Tsai et al19 reported that the CAR at weeks 9 to 24
with varenicline versus placebo was 46.8% versus
21.8% (OR ⫽ 3.38; 95% CI, 1.9 –5.99; P ⬍ 0.001) in
a cohort of Korean and Taiwanese smokers. Although
the abstinence rate in the group receiving the active
474
drug was higher than that in the present study, there
was a high abstinence rate in the placebo group as well,
which negatively affected the OR. In another study,
conducted by Wang et al20 in a population from China,
Singapore, and Thailand, the abstinence rates were
38.2% and 25.0% with active treatment and placebo,
respectively (OR ⫽ 1.92; 95% CI, 1.18 –3.13; P ⫽
0.0080). Higher placebo effects were observed in these
2 studies compared with that in the present study.
In the present study, the likelihood of quitting smoking
with varenicline was higher compared with those in 2
previously reported meta-analyses.4,21 The first, published by the US Department of Health and Human Services, Public Health Service, reported an estimated
pooled OR of 3.1 (95% CI, 2.5–3.8) for studies comparing the effects of varenicline 2 mg/d with those of placebo
at 6 months after quit date compared with an OR ⫽ 4.78
at weeks 9 to 24 in the present study.4 In a Cochrane
systematic review of 6 randomized, controlled trials investigating nicotine receptor partial agonists, varenicline
was reported to be associated with a significant (⬃3-fold)
Volume 33 Number 4
C T. Bolliger et al.
increase in CAR at 12 months versus placebo (pooled
OR ⫽ 3.22; 95% CI, 2.43– 4.27).21 However, the longer duration of the trials included in the Cochrane
meta-analysis makes a direct comparison with the results from the present 24-week study difficult.
Meaning of the Study
The apparently greater likelihood of quitting smoking
with varenicline compared with placebo observed in the
present study might be attributable to the limited access
to smoking-cessation interventions generally available in
Latin American, African, and Middle Eastern countries.
Of note is the low percentage of smokers with previous
quit attempts in this study—more than half of participants had made no serious prior quit attempt (54.4% in
the varenicline arm; 55.1% in the placebo arm). The
FTND scores in these participants were high, reflecting a
high degree of nicotine dependence.
The results from this study suggest that varenicline
was well tolerated, with a safety profile similar to those in
observations from previously published studies. As in
previous studies, the most frequently reported AEs were
nausea, headache, and insomnia, reported at frequencies
comparable to those from previously published varenicline trials.6,16 Anxiety was reported in fewer participants
on active treatment compared with placebo (4.1% vs
7.6%), although this difference has not been tested for
statistical inferences. Overall, this study further adds to
the growing database of clinical trials the results of which
suggest that varenicline is well tolerated.
There have been postmarketing reports of serious neuropsychiatric symptoms in smokers taking varenicline,
including suicidal thoughts and attempts and completed
suicides. In 2009, varenicline received a “boxed warning” regarding neuropsychiatric SAEs. In the United
States, a nonprofit group called the Institute of Safe Medication Practices issued several reports regarding the
safety of varenicline based on neuropsychiatric postmarketing reports and called for restrictions on its use.22,23 A
published review of varenicline tolerability by a Veterans
Affairs Health System in the United States recommended
that, based on the numerous reported AEs and published
case studies, selective initiation of varenicline and close
follow-up are warranted, especially in subjects with preexisting psychiatric illness.24 Due to the potential for
these types of events, continued medical research into the
neuropsychiatric safety profile of varenicline is essential.
To understand the potential risk based on data from
randomized clinical trials, Tonstad et al25 conducted a
April 2011
systematic, quantitative review of 10 placebo-controlled trials in smokers with no current or recent psychiatric disorder. The study reported risk differences
for psychiatric disorders ⬍1.0% between the varenicline and placebo groups, with the exception of sleep
disorders and disturbances, which were increased by
10% (95% CI, 7.9 to 12.3) in the varenicline group.
The highest risk increase was 0.8% (95% CI, – 0.06 to
1.67) for depressed mood disorders and disturbances
in the varenicline group versus placebo. The rate of
suicidal and self-injurious behaviors was 0.12% (95%
CI, – 0.27 to 0.04) higher in the placebo group compared with the active-treatment arm. The 10 studies
used in that review were not designed to differentiate
between abstinence and medication effects.
Strengths and Limitations of the Study
The results from this study suggest that varenicline
is an effective smoking-cessation aid in participants
from Latin American, African, and Middle Eastern
countries. Results suggest consistency across the regions. Limitations of this study were the stringent participant exclusion criteria, which, while necessary for
this study in these populations, limit the generalizability of the results across wider smoking populations.
Race identity data were collected according to a selfreporting method by the participants and therefore the
authors cannot make more specific conclusions on
smoking and race or ethnicities. In addition, the participants were found to have wide ranges of weight and
body mass index values at baseline, although the few
participants with higher values were outliers. Consequently, caution should be used in interpreting these
results across participants. Differences in varenicline
experience were reported in lower-weight subjects in a
previously published pharmacokinetic study.26 The
variability in health care access, and population demography and characteristics, restrict a more definite
extrapolation of the study results across regions and,
more specifically, across countries.
Future Research
As this study was conducted at selected sites in Latin
America, Africa, and the Middle East, which have large
socioeconomic differences and widely varying smoking
prevalence, it is interesting to compare the efficacy outcomes between regions. The results (not shown) seem
to indicate that there are no relevant differences between the individual regions. However, the study was
475
Clinical Therapeutics
limited in that it was powered only for an efficacy analysis, and therefore did not allow for statistical conclusions for a safety subanalysis. Looking at additional
regional effects would be of interest in future studies.
CONCLUSION
Varenicline was efficacious as an aid for smoking cessation but was associated with a numerically larger
number of AEs compared with placebo in these adult
smokers from 11 countries in Latin America, Africa,
and the Middle East.
ACKNOWLEDGMENTS
This work was supported by Pfizer Inc, which was the sponsor and funding source for the clinical trial reported here.
All of the authors completed the Unified Competing Interest form at www.icmje.org/coi_disclosure.pdf (available
on request from the corresponding author) and declare that:
(1) the institutions of Drs. Bolliger, Issa, Posadas-Valay,
and Safwat received financial support from Pfizer for the
clinical trial; (2) Drs. Bolliger, Issa, Posadas-Valay, and
Safwat received no financial support from Pfizer for the
submitted work; (3) Drs. Bolliger, Issa, Posadas-Valay,
and Safwat have specified relationships with Pfizer that
might have an interest in the submitted work in the previous 3 years, including investigator payments, consulting honoraria, and grants; (4) their spouses, partners, and
children have no financial relationships that may be relevant to the submitted work; and (5) Drs. Bolliger, Issa,
Posadas-Valay, and Safwat have no nonfinancial interests
that may be relevant to the submitted work.
Drs. Bolliger, Issa, Posadas-Valay, and Safwat did
not receive financial support with respect to the writing
or development of the manuscript. Dr. Abreu, Mr.
Correia, Dr. Park, and Mr. Chopra are employees of,
and stockholders in, Pfizer.
Dr. Abreu and Mr. Chopra participated in the design of the study. Drs. Bolliger, Issa, Posadas-Valay,
and Safwat participated in the collection of data. Dr.
Abreu, Mr. Correia, and Mr. Chopra were involved in
data analysis. All of the authors were involved in interpretation of data, drafting the article, reviewing the
article for important intellectual content, and the decision to submit the article for publication. Drs. Bolliger,
Issa, Posadas-Valay, and Safwat acted as investigators
for this study and were remunerated for this role. They
did not receive honoraria for this publication. All of the
authors had full access to all of the data (including statistical reports and tables) in the study and are responsible
476
for the integrity of the data and the accuracy of the data
analysis. Dr. Bolliger was the guarantor of the study.
Pfizer was involved in study design; in the collection,
analysis, and interpretation of data; in the writing of the
report; and in the decision to submit the article for publication. Editorial assistance (proofreading, collation of
review comments, formatting the manuscript for submission, preparation of figures, and formatting of references)
was provided by Penny Gorringe, MSc, and Fiona
Nitsche, PhD, of UBC Scientific Solutions and was
funded by Pfizer.
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Address correspondence to: Chris T. Bolliger, MD, PhD, Respiratory Research Unit, Faculty of Health Sciences, University of Stellenbosch, Cape
Town, 7505 South Africa. E-mail: [email protected]
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